Abstract (Summary): Spinal cord injury (SCI) often causes permanent paralysis due to failure of injured axons to regenerate. Although injured CS axons do not re-grow beyond the lesion after SCI, they form new connections with propriospinal neurons above (rostral to) the lesion which contributes to the limited recovery seen in these injury models. In this study, we propose two-pronged strategies to simultaneously induce re- growth of injured corticospinal (CS) axons beyond the lesion site and enhance remodeling of connectivity between injured CS axons and propriospinal neurons after SCI. CS axonal growth can be promoted by reducing phosphatase and tensin homolog (Pten) activity in the sensorimotor cortex. Our preliminary data reveal increased CS connectivity after SC in mice lacking PlexA1 encoding a semaphorin6D receptor. Since injured CS axons in PlexA1 mutants do not pass beyond the lesion site, our preliminary data strongly suggest that new connections between injured CS axons and propriospinal neurons are enhanced through the uninjured ventral regions after SCI to compensate for the loss of CS inputs. Based on these preliminary data, the central hypothesis of this proposal is that a combined modulation of Sema6D-PlexA1 and Pten signaling will facilitate rewiring of CS connectivity with propriospinal neurons as well as re-growth of injured CS axons after SCI at cervical levels. Therefore, these interventions will improve functional CS connectivity and motor recovery. In Aim 1, we will determine whether deletion of both PlexA1 and Pten in the sensorimotor cortex will enhance connectivity between injured CS axons and propriospinal neurons to a greater degree than the loss of PlexA1 or Pten alone. In Aim 2, we will determine whether PlexA1, Pten, or PlexA1/Pten deletion increases circuits between injured CS neurons and muscles. Finally, in Aim 3, we will examine whether motor recovery is enhanced in mice lacking PlexA1 and Pten in the sensorimotor cortex.